CH 4 CNS DRUGS PART 1

Overview CNS Drugs and Antipsychotics

CNS

it includes everything in the brain and areas which are outside the autonomic nervous system

DRUGS AFFECTING THE CNS

antipsychotics, sedative, anxiolytics, antidepressants, anti-seizures, anesthetic agents, and central dopaminergic signaling agents

2 TYPES OF ANTIPSYCHOTICS

typical and atypical

TYPICAL ANTIPSYCHOTICS

classical, traditional, 1st generation (has side effects)

ATYPICAL ANTIPSYCHOTICS

2nd generation, lesser side effects

ANTI-SEIZURES

may also include anti-Parkinsons

2 TYPES OF ANESTHETIC AGENTS

local and general

LOCAL ANESTHETIC AGENT

used for wounds, minor surgery (eg. dental), stitches

GENERAL ANESTHETIC AGENT

used in surgical operations

CENTRAL DOPAMINERGIC SIGNALING AGENTS

either block or nagiinduce (eg. GABA, 5HT [serotonin])

PSYCHOSES

one of the most severe mental illnesses, symptoms: delusions and hallucinations, with anxiety disorders; inability to comprehend reality with mood, thought, and behavioral dysfunction

PSYCHOSES COMMON DISORDERS

delirium and dementia; schizophrenia & other psychotic illnesses, and manic phase of manic-depressive disorder

DELUSIONS

extreme sense of false belief (eg. paranoia)

SENSORY HALLUCINATIONS

most common is auditory hallucinations

DELIRIUM

hallucination but more on visionary things (not FDA approved indication)

SCHIZOPHRENIA

described as having a clear sensorium but with marked thinking disorder

2 SETS OF SYMPTOMS OF SCHIZOPHRENIA

positive and negative

POSITIVE SYMPTOMS OF SCHIZOPHRENIA

delusions, hallucinations, and disorganized speech

NEGATIVE SYMPTOMS OF SCHIZOPHRENIA

flat affect (very low emotional response), apathy

[ less common, mas mahirap itreat ]

SCHIZOPHRENIA PRIMARY HYPOTHESIS FOR ETIOLOGY

very high levels of dopaminergic transmission

[ drugs usually target/block D2-type dopamine receptors ]

PHENOTHIAZINES & BUTYROPHENONES

typical antipsychotics

MOA OF TYPICAL ANTIPSYCHOTICS

direct interaction with D2-type receptors;

combines inverse agonist, antagonist, partial agonist acitvity to provide spectrum of effects

EPS

extrapyramidal syndrome

EPS of PHENOTHIAZINES & BUTYROPHENONES

dystonia (spasms), akathisia (motor restlessness), parkinsonian effect, and tardive dyskinesia (irregular jerking movement)

PHENOTHIAZINES: trans alpha-rotamer conformation

D2-type receptor binding

PHENOTHIAZINES: N-atoms on the ring and side chain

essential for antipsychotic action; must be separated by 3 carbons

PHENOTHIAZINE W 2 CARBONS

used as an antihistamine/sedative action [ Promethazine (Phenergan) ]

PHENOTHIAZINE: side chains (R2 and R3)

can be aliphatic aminopropyl, piperidine ring, or piperazine ring (highest potency and activity)

PHENOTHIAZINE: C2 (R1)

must have an electronegative atom or electron-withdrawing group — essential to activity

PHENOTHIAZINE: N10-C11

can be replaced with C=C (in cis form) for greater activity (eg. thiothixene)

PHENOTHIAZINE: free -OH in the side chain moiety

(eg. fluphenazine) can yield stable, lipophilic ester with longer DOA

-AZINE; -PERIDOL

what typical phenothiazine antipsychotics usually end with

PHENOTHIAZINE: DOPAMINE

trans alpha-rotamer

PHENOTHIAZINE: CHLORPROMAZINE

protoype phenothiazine;

aliphatic aminopropyl side chain

PHENOTHIAZINE: THIORIDAZINE

methylthio (R1);

piperidine phenothiazine

PHENOTHIAZINE: FLUPHENAZINE

-OH side chain moiety;

piperazine phenothiazine

PHENOTHIAZINE: THIOTHIXENE

C10-11 double bond;

piperazine phenothiazine

PHARMACOLOGIC PROFILES: Antipsychotic Potency & EPS Frequency

Piperazines > Piperidines > Aliphatics

PHARMACOLOGIC PROFILES: Sedation

Aliphatics = Piperidines > Piperazines

PHARMACOLOGIC PROFILES: Hypotension

Aliphatics > Piperidines > Piperazines

PHENOTHIAZINES: Metabolism

N-dealkylation, Aromatic hydroxylation at C7, S-oxidation, Ester hydrolysis (only for Fluphenazine), CYP 3A4 (for Pimozide)

BUTYROPHENONES: C4 Tertiary Amino (C4 3* N) of the skeleton

essential for activity

BUTYROPHENONES: Y (Carbonyl) position replaced with: thioketone, olefinic, phenoxy or reduction

decrease potency

BUTYROPHENONES: Y (Carbonyl) position replaced with: 4-fluorophenyl

increase potency

BUTYROPHENONES: X position replaced with -F at -para position of benzene

maximum potency

-PERIDOL; -PERIDONE

what typical butyrophenone antipsychotics usually end with

BUTYROPHENONE: HALOPERIDOL

prototype butyrophenone

BUTYROPHENONE: RISPERIDONE

has benzisoxazole ring; di directly attached yung F

[ treats positive & negative symptoms of Schizophrenia ]

BUTYROPHENONE: DROPERIDOL

has benzimidazoline ring;

[ used as preanesthetic neuroleptic ]

BUTYROPHENONE: PIMOZIDE

has 4-fluorophenyl ring

[ used as preanesthetic neuroleptic ]

3 ATYPICAL ANTIPSYCHOTICS

diarylazepine derivatives, benzisoxazole / benzisothiazoles, & arylpiperazine quinolinone

-XAPINE; -ZAPINE

what atypical diarylazepine derivatives antipsychotics end with

DIARYLDIAZEPINE PHARMACOPHORE

reduces positive & negative symptoms;

improves cognitive function

MOA OF DIARYLAZEPINE DERIVATIVES

direct D2-type antagonism + partial D2-type agonism;

5-HT2 receptor antagonism (reduced EPS)

DIARYLAZEPINE DERIVATIVES: Metabolism

Oxidation, N-dealkylation, Conjugation, CYP 1A2, CYP 3A4

DIARYLAZEPINE DERIVATIVES: CLOZAPINE

dibenzodiazepine derivative

[ used to decrease hallucinations and helps in preventing suicide attempts ]

DIARYLAZEPINE DERIVATIVES: OLANZAPINE

clozapine analog; more potent D2 antagonism

[ used also for bipolar disorder and depression ]

DIARYLAZEPINE DERIVATIVES: QUETIAPINE

clozapine analog

[ used for bipolar disorders; has mood-improving effects ]

BENZISOXAZOLE

Y = O

BENZISOTHIAZOLE

Y = S

MOA OF BENZISOXAZOLE / BENZISOTHIAZOLE

similar with diarylazepines but with higher affinity and antagonism at 5-HT2 receptors

BENZISOXAZOLE / BENZISOTHIAZOLE: Metabolism

CYP 2D6 and 3A4: Risperidone & Iloperidone, Ziprasidone (3A4 only)

keto reduction: Iloperidone; N-dealkylation - Lurasidone

ZIPRASIDONE

Y = S;

X = N;

Z = H

TIOSPIRONE

Y = S;

X = N;

Z = H

RISPERIDONE

Y = O;

X = CH;

Z = F;

W = H

PALIPERIDONE

Y = O;

X = CH;

Z = F;

W = OH

ILOPERIDONE

Y = O;

X = CH;

Z = F

LURASIDONE

Y = S;

X = N;

Z = H

ARIPIPRAZOLE

only drug in the arylpiperazine quinolinone group;

has high oral bioavailability;

highly protein bound, longer DOA

MOA OF ARYLPIPERAZINE QUINOLINONE

high affinity for D2-type receptors (partial agonist) & serotonin (5-HT) GPCRs

ARYLPIPERAZINE QUINOLINONE: Metabolism

CYP 2D6 & 3A4